Polymer no donor predrug nanofiber coating for medical devices and therapy

ABSTRACT

The present invention relates to nanofibers that produce therapeutic amounts of nitric oxide after a delay period, which allows time to install or implant the device into a patient. The nitric oxide release is thus localized to the area of the organism where NO dosing is indicated. The delay time is achieved by cospinning the NO-producing fiber with a fiber that tends to sequester the former&#39;s NO-producing functional groups. Fibers of the present invention may be incorporated into medical devices such as stents or other implantable medical devices to prevent the formation of adhesions or scarring in the area of the implant.

BACKGROUND OF THE INVENTION

The present invention relates to coatings and medical devices thatdeliver therapeutic amounts of nitric oxide (NO) to areas where NOdosing is indicated. More particularly, the present invention relates tofibrous materials that evolve nitric oxide after a delayed activation.The nanofibers of the present invention function to both carry andsequester reagents, which can react to release NO gas, when water, bloodor other fluids known as activators are brought into contact with thenanofiber. The sequestration action slows the diffusion of activators toan NO precursor and thus delays the precursor's conversion to NO.

NO is known to inhibit the aggregation of platelets and to reduce smoothmuscle proliferation, which is known to reduce restenosis. Whendelivered directly to a particular site, it has been shown to prevent orreduce inflammation at the site where medical personnel have introducedforeign objects or devices into the patient, such as stents or otherimplantable devices.

Researchers have sought various ways to deliver NO to damaged tissue andto tissues and organs at risk of injury. NO can be deliveredsystemically, but such delivery can bring undesired side effects with itU.S. Pat. No. 5,814,656. Ideally, NO should be delivered in a controlledmanner specifically to those tissues and organs that have been injuredor are at risk of injury. The present invention fills this need byproviding a coatings and medical devices that release NO after a delay,which gives the physician time to implant the device. Thus, for the mostpart only tissues requiring NO treatment receive doses of NO.

Insoluble polymeric NONOates have also been generally described in Smithet al. U.S. Pat. No. 5,519,020 to topically deliver NO to specifictissues. However, this patent does not discuss impeding activation suchthat there is substantially a delay between the time the device is firstapplied and the time when NO production becomes significant. The use ofpolymeric NONOates as coatings on implantable medical devices is alsodisclosed in Stamler et al. U.S. Pat. No. 5,770,645. This patent issimilarly deficient in that it too fails to discuss any mode of delayingnitric oxide production. The device of ‘645 is essentially active fromthe moment it is first implanted because it lacks an activator-impedingelement. In contrast, the present invention incorporates just such anelement, which is specifically directed to slowing or delaying theactivation of the nitric oxide predrug.

Probably, the most closely related art is the inventors' own U.S. Pat.No. 6,737,447, which discloses a polymeric coating for medical devicesthat releases nitric oxide in a controlled manner. However, thedistinction between this and the present invention is that ‘447’s modeof controlled release is its use of bisepoxide to crosslink the coatingthus constricting that material's porosity thus slowing the diffusion ofactivators into and nitric oxide out of the coating. In contrast thepresent invention utilizes a second fiber having either a morehydrophobic character, or a buffering effect to impede, slow or delaythe activation of the nitric oxide precursor.

SUMMARY OF THE INVENTION

The present invention relates to coatings and medical devices thatdeliver therapeutic amounts of nitric oxide (NO) to areas where NOdosing is indicated. More particularly, the present invention relates tofibrous materials that evolve nitric oxide after a delayed activation.The nanofibers of the present invention function to both carry, andsequester and/or buffer the environment surrounding NO precursor(hereinafter referred to as a predrug) reagents, which release NO whenwater, blood or other fluids known as activators are brought intocontact with the precursor. The sequestration action slows the diffusionof activators to an NO precursor and thus delays the precursor'sconversion to NO, and it results from the hydrophobic character of thesecond fiber. Additionally, the buffering action creates a more basicenvironment immediately surrounding the NO precursor, which results in aslower conversion rate to nitric oxide. In any given embodiment eitherthe sequestration or the buffering effect, or both may be used to impedeNO production. In any case both the sequestration and buffering effectsarise from the incorporation of a fiber hereinafter referred to as a“second fiber”.

The present invention uses a smaller amount of NO predrug than priorinnovations to produce an effective amount of NO because it is spatiallyconstrained to the locus where NO dosing is indicated, whereas someprior innovations have allowed NO to circulate in the blood stream.Thus, in relatively small quantities the present invention could evolvetherapeutic amounts of NO and may be useful as a stent coating, aballoon used to open the stent, catheters, in products such as wounddressings for the treatment of fungal or parasitic infections, or fortreatment of poorly healing wounds.

The central concept of the present invention could be applied in otherareas, namely CO or peroxide production, sterilization, and chemicaltherapies. Particularly, using a second fiber to sequester a precursorcompound thus impeding an activator's access thereto and thus delayingthe release of a product compound could be applied in other areas,namely CO or peroxide production, sterilization, and chemical therapies.

The present invention relates to a medical device comprising a polymericcarrier fiber component, a nitric oxide predrug component, and a secondfiber functioning to sequester the predrug from activating species. Thepresent invention further relates to a medical device, wherein themedical device is selected from the group consisting of a vasculargraft, a stent, a catheter, a wound dressing, and a surgical thread. Thepresent invention further relates to a medical device, wherein thepolymeric carrier fiber component comprises at least one secondary aminemoiety. The present invention further relates to a medical device,wherein the polymeric carrier fiber component is selected from the groupconsisting of a polyethyleneimine, a polyethyleneimine grafted to apolysaccharide backbone, and a poly(ethyleneimine) salt. The presentinvention further relates to a medical device, wherein the polymericcarrier fiber component comprises a poly(ethyleneimine) fiber. Thepresent invention further relates to a medical device, wherein thepolymeric carrier fiber component comprises an electrospun nanofiber.The present invention further relates to a medical device, wherein thenitric oxide predrug component is selected from the group consisting ofa diazeniumdiolate, an O-alkylated diazeniumdiolate, and anO-derivatized diazeniumdiolate. The present invention further relates toa medical device, wherein the nitric oxide predrug component comprises adiazeniumdiolate. The present invention further relates to a medicaldevice further comprising an activator. The present invention furtherrelates to a medical device, wherein the activator is a proton donor.The present invention further relates to a medical device, wherein theactivator is a buffer selected from the group consisting of phosphates,succinates, carbonates, acetates, formates, propionates, butyrates,fatty acids, and amino acids. The present invention further relates to amedical device, wherein the activator is water. The present inventionfurther relates to a medical device further comprising a mobile phase.The present invention further relates to a medical device, wherein themobile phase is capable of transporting an activator such that itcontacts the nitric oxide predrug component. The present inventionfurther relates to a medical device, wherein the mobile phase isselected from the group consisting of water, methanol, ethanol,propanols, butanols, pentanols, hexanols, phenols, naphthols, polyols,acetic acid, N,N-dimethylformamide, dimethyl sulfoxide,dimethylacetamide, and tetrahydrofuran, hexanethylphosphoramide. Thepresent invention further relates to a medical device further comprisinga substantially hydrophobic second fiber. The present invention furtherrelates to a medical device, wherein the second fiber is selected fromthe group consisting of polyurethane, polyamide, polyethylene,polypropylene, polyesters, saturated polyesters, polyethyleneterephthalate, polytetrafluoroethylene, perfluoroethylene, polystyrene,polyvinyl chloride, and polyvinyl pyrolidone.

The following terms are specially defined. Predrug, as used herein,means any compound that will be modified to form a drug species, whereinthe modification may take place either inside or outside of the body,and either before or after the predrug reaches the area of the bodywhere administration of the drug is indicated. Polymeric carrier fibercomponent comprises at least one of any fiber capable of reversiblyreacting with nitric oxide to form functional groups, located on thefiber, that amount to nitric oxide predrug components. Second fibercomponent, as used herein, refers to one or more fibers that sequesterthe predrug from activating agents such as blood or lymph while thedevice is being inserted or implanted into, or otherwise applied to thepatient. The term activator comprises any compound that stimulates thenitric oxide predrug component to produce nitric oxide.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present invention is directed to a coating and device that producesa therapeutic amount of nitric oxide and delivers it to areas of anorganism where NO dosing is indicated. In general, the present inventiontakes the form of a mixture of fibers. Some of the fibers of the mixtureare derivatized so that they will evolve NO when stimulated to do so.Importantly, other “second” fibers are not derivatized, rather theirpurpose is to provide structure to the mixture of fibers and/or tosequester the NO yielding portions of the derivatized fibers fromspecies that tend to stimulate NO evolution. Alternatively, theirfunction is to buffer the environment of the NO predrug so as to slowits conversion to NO. In doing so the second fiber tends to regulate therate at which NO evolves from the invention, and impedes activation ofthe device's constituent NO-yielding moieties.

An illustrative embodiment of the present invention comprises a coatingon a metal stent for opening a blood vessel. Such a device must beimplanted in a patient by feeding it through a blood vessel beginningfrom a point some distance away from the area where the stent willultimately reside. Therefore the tissues at the point of insertion areat some distance from the site where nitric oxide dosing is indicated.Thus tissues at the insertion point, as well as all points betweeninsertion and the locus where the stent is ultimately implanted, arepreferably not exposed to NO. The present invention accomplishes thisthrough the foregoing built-in NO production delay.

In general, the present invention comprises three elements: (1) apolymeric carrier fiber component, (2) a nitric oxide predrug, and (3) asecond fiber component. The polymeric carrier fiber component comprisesany fiber or fiber having sites capable of reversibly reacting withnitric oxide to form functional groups, located on the fiber, thatamount to nitric oxide predrug components. Acceptable fibers tend tocontain secondary amine moieties inasmuch as secondary amines are knownto react with nitric oxide to form diazeniumdiolates, which undergo afirst order reaction evolving nitric oxide. In order to stimulate the NOevolving reaction the nitric oxide predrug component, i.e. thediazeniumdiolate for example, must chemically contact and interact witha source of protons hereinafter referred to as an activator. It isexpected that many classes of compounds can be activators inasmuch asonly very minimal Bronsted acidity is necessary to stimulate thedecomposition reaction. Thus water, alcohols, polyols and the like areall acidic enough to act as activators. Other activator species includebody fluids, especially blood, lymph, bile and the like. In order tosubstantially restrict NO exposure to those areas where NO dosing isindicated activation is impeded to allow for the time required toimplant or insert the device into the patient. Such impedance isachieved through the action of the second fiber, which either sequestersthe predrug from species that tend to stimulate the predrug-to-drugreaction, or buffers the environment around the predrug so as to slowthe rate of its conversion to drug form. Preferably, the three elementsof the present invention can comprise a single fiber in that the fiberfunctions as a carrier, includes the predrug, and has a “second” fibercomponent that provides structure and/or sequesters the predrug. But theelements can be provided as two or three separate components.

Polymeric Carrier Fiber Components

The polymeric carrier fiber component comprises any fiber capable ofreversibly reacting with nitric oxide to form functional groups, locatedon the fiber, that amount to nitric oxide predrug components. Acceptablefibers tend to contain secondary amine moieties inasmuch as secondaryamines are known to react with nitric oxide to form diazeniumdiolates,which undergo a first order reaction evolving nitric oxide (I-II).Acceptable carrier fiber components comprise polymers including but notlimited to polyetyleneimine, polypropyleneimines, polybutyleneimines,polyurethanes, and polyamides. Further acceptable carrier fibercomponents include any of the foregoing polymers grafted to an inertbackbone, e.g. polyethyleneimine grafted to a an otherwise relativelyinert backbone such as a polysaccharide backbone, especially acellulosic backbone. Still further acceptable carrier fiber componentsinclude any fiberizable material comprising secondary amine moieties.

A preferred material for forming a carrier fiber component in accordancewith the present invention is high density linear polyethyleneimine(I-II) having a weight average molecular weight of greater than about200,000. Linear PEI is soluble in common solvents like water andethanol. PEI fibers may be formed by electrospinning processes known inthe art. It will also be appreciated by those skilled in the art thatPEI fibers may be formed in accordance with the present invention bymethods other than electrospinning. Any method of forming organicpolymers into fibers known in the art may be used. For instance,extrusion methods such as wet spinning, dry spinning, melt spinning, andgel spinning are all acceptable methods of forming fibers in accord withthe present invention. Generally, finer denier fibers yield fiber matshaving greater surface area and thus more nitric oxide predrug moieties,which generally results in better performance. Accordingly,electrospinning is the preferred method of manufacturing PEI fibers.

In general the present invention may take the form of a nonwoven fibermat wherein polymeric carrier fibers and second fibers are cospun sothat they are more or less randomly distributed. The present inventionmay also take the form of a layered nonwoven fiber mat, wherein thecarrier fiber is spun onto a substrate and then substantially coveredand sequestered by spinning a second fiber. In either case the nonwovenfiber mat may take the form of a coating on a medical device such as astent.

Nitric Oxide Predrug Components

In the most general terms, the nitric oxide predrug component of thepresent invention comprises any chemical entity that yields nitric oxidewhen stimulated to do so by an activator of the present invention. It isappreciated in the art that these predrug components may take severalforms including but not limited to diazeniumdiolates (sometimes referredto as NONOates). It is further appreciated in the art that these predrugcomponents may take the form of O-alkylated diazeniumdiolate, or anyO-derivatized diazeniumdiolate where the O-derivative may be convertedback to the diazeniumdiolates. Such O-derivatized NONOates are generallymore stable than salts. Particularly, the energy of activation of thedecomposition reaction is generally substantially higher than that ofthe non-O-derivatized form. Thus, the derivative tends to either notevolve NO in the absence of an enzymatic activator, or to extend thehalf-life of the NONOate significantly. The non-O-derivatizeddiazeniumdiolate functional group, i.e. the salt, is a preferred nitricoxide predrug component of the present invention, and is known todecompose by a first order mechanism in the presence of a proton source,i.e. activators.

Reacting PEI with NO ordinarily results in the formation ofdiazeniumdiolates, which causes the PEI to lose its solubility inethanol, and in some cases become insoluble in water. When the NOmodified PEI polymers are exposed to water they begin to decompose inpredictable ways resulting in the release of NO. A typical NO releaseprofile from a PEI fiber mat is generally short, one to two days being arepresentative time.

Activators

Generally, activators comprise any compound that stimulates the nitricoxide predrug component to produce nitric oxide. Where diazeniumdiolateis the predrug, acceptable activators comprise proton sources, i.e.Bronsted acids. Representative activators consistent with the presentinvention include without limitation: water, body fluids such as blood,lymph, bile and the like; and methanol, ethanol, propanols, butanols,pentanols, hexanols, phenols, naphthols, polyols, and the like. Furtheractivators within the scope of the present invention comprise commonaqueous acidic buffers including without limitation phosphates,succinates, carbonates, acetates, formates, propionates, butyrates,fatty acids, and amino acids, and the like. Preferred activators includewithout limitation: water, body fluids such as blood or lymph, alcohols,and common aqueous acidic buffer solutions.

Mobile Phases

It will be appreciated by those skilled in the art that the nitric oxidepredrug component and the activator may be spatially separated in amanner that requires a mobile fluid to carry the activator to thepredrug and thus stimulate the reaction. Hereinafter such fluids arereferred to as mobile phases. In many cases the activator is itself afluid under ordinary operating conditions so an additional carrier fluidis not necessary. In such cases the mobile phase may be omitted.Acceptable mobile phases include any fluid that is capable oftransporting an activator to a predrug component in a manner that placesthe activator in physicochemical contact with the predrug so that thenitric oxide yielding reaction is enabled.

Mobile phases are a component of the present invention, which are onlyrequired when the activator is unable to reach the nitric oxide predrugcomponent without assistance. In general, the mobile phase carries theactivator to the nitric oxide predrug so that the two makephysicochemical contact resulting in the evolution of nitric oxide. Thusit follows that mobile phases do not principally participate in thedecomposition in the manner of a catalyst or reagent, rater they areprincipally activator delivery vehicles. However, the fact that acompound is capable of stimulating the predrug's NO evolution does notprevent it from being classified as a mobile phase as well. For example,water is acidic enough to cause a NONOate to evolve NO, but it may alsodissolve and carry an activator such as phosphate to the NONOate predrugthus acting as a delivery vehicle for phosphate. Accordingly, water maybe doubly classified as both an activator and a mobile phase.

Acceptable mobile phases comprise fluids, preferably liquids, capable ofcarrying activators to the predrug component. More particularly, mobilephases within the purview of the present invention are liquids capableof dissolving activators. Still more particularly, wherediazeniumdiolates are the predrug component, the mobile phase ispreferably a more or less polar liquid, especially polar solvents suchas water, methanol, ethanol, propanols, butanols, pentanols, hexanols,phenols, naphthols, polyols, acetic acid, N,N-dimethylformamide,dimethyl sulfoxide, dimethylacetamide, and tetrahydrofuran,hexamethylphosphoramide, and the like.

Second Fibers

The function of second fibers is to sequester the predrug fromactivating agents, buffer the area surrounding the NO predrug, or boththus slowing the predrug's conversion to drug form. Accordingly, secondfibers may have substantial hydrophobic character. In this way theyamount to a physical barrier that the activator must cross in order toreact with the predrug and release NO. Alternatively, the second fibermay have basic functional groups that render the environment surroundingthe NO predrug more basic thereby slowing its conversion to drug form.Thus, NO production is substantially limited to the area of the patientwhere NO dosing is indicated.

Second fibers are also in part used to dilute the NO-releasing fibers,i.e. the polymeric carrier fiber component. Often the output of theNO-releasing fibers is too rapid to create a coating or devicecomprising them alone. Rather, it would often make sense to embed orcospin the NO-producing fibers into a matrix of fibers made from anotherpolymer, i.e. the second fibers. Appropriate materials for second fibersdepends upon the application, but in general they are chosen based upontheir capacity to sequester the predrug from activators as well asmechanical durability, and biodegradability properties.

Additionally, second fibers may be structural fibers in the sense thatthey may add strength to the materials allowing it to be formed intovarious objects such as a free-standing patch, tube or the like.

Polymers from which second fibers may be made include without limitationpolyurethane, polyamide, polyethylene, polypropylene, polyesters,saturated polyesters, polyethylene terephthalate,polytetrafluoroethylene, perfluoroethylene, polystyrene, polyvinylchloride, and polyvinyl pyrolidone. Preferably the second fiber issubstantially hydrophobic.

Consider a stent coating as an illustration of the function of secondfibers. A stent coated only with NO modified PEI fibers would have arapid NO output. Therefore the coating would substantially exposetissues to NO that are not at risk of injury and for which NO dosing isnot indicated. In contrast, if a polyurethane such as TECOPHILIC iselectrospun with the PEI to form a stent coating, the PEI's NONOatefunctional groups do not contact the patient's blood immediately becauseit takes time for the aqueous body fluids to penetrate the polyurethanedoped coating.¹ ¹TECOPHILIC is a trademark of Noveon IP Holdings Corpdenoting thermoplastic polyurethane compounds for use in the manufactureof hydrophilic plastic articles

In a preferred embodiment polyethyleneimine nanofibers are electrospunonto a medical device or device component along with polyurethane secondfibers. The nanofibers are then exposed to NO gas such that at least aportion of the PEI's secondary amine moieties react with NO to formdiazeniumdiolate functional groups. In another preferred embodiment thePEI is exposed to NO prior to electrospinning, thus the electrospun PEIfiber already contains diazeniumdiolate functional groups. In eithercase the PEI's NONOate functional groups are sequestered by thepolyurethane nanofiber and thus shielded from moisture and otheractivators until the device is implanted. NO gas evolves upon exposureto biological fluids such as blood, lymph, or sweat; or upon exposure toother activators such as physiological buffers, alcohols, or polyols.

In another embodiment any of the foregoing fibers may be spun onto anymedical device including but not limited to stents, angioplastyballoons, catheters, and the like. The fibers may also be spun intononwoven fiber mats as in, for example, transdermal patches, bandagesand the like. In still another embodiment the nitric oxide-yieldingentity may be sequestered within the polymeric carrier fiber as in themanner of a precipitate. In still another embodiment fiber denier iscontrolled so as to regulate the output of NO. For instance smallerdiameter fibers may contain more nitric acid predrug component thussmaller diameter fibers tend to have a higher NO output. In stillanother embodiment the second fibers comprise biodegradable orbioabsorbable materials so that a device or portion thereof made withsuch second fibers tends to be consumed by the subject organism's ownbody. In still another embodiment the present invention takes the formof a vascular graft. Another embodiment of the present invention takesthe form of a catheter. Still another embodiment of the presentinvention is a wound dressing as in the manner of a bandage.

In order to demonstrate the practice of the present invention, thefollowing example is provided. The embodiments should not, however, beviewed as limiting the scope of the invention. The claims will serve todefine the invention.

The synthesis of linear polyethylenimine (L-PEI) was performed in a 2 Lthree-necked round-bottomed flask with a drain stopcock in the bottom;it was equipped with a thermometer well, reflux condenser, additionfunnel, stirrer, and heating mantle. With rapid stirring of 300 mldeionized water, the Poly (2-ethyl-2-ozaxoline) or polyethyloxazoline500,000 MW (49.6 g, 0.5 mol base) was slowly added, and the mixture wasstirred at room temperature for several hours until the polymer haddissolved. To the stirred solution was slowly added 75 g (0.75 mol)sulfuric acid; the mixture was then stirred under 100° C. reflux. After18 h, the agitation was increased and 200 ml additional deionized waterwas added. A distilling head was placed on the flask and about 250 ml ofthe distillate (water and propionic acid) was removed.

At reflux, 250 ml of 50% of sodium hydroxide was added with stirringover 15 min. A viscous yellow (light cream color) polymer phase stuck tothe stirrer shaft, and 200 ml deionized water was added. The causticlayer was drained off, and the polymer mass was stirred with 500 mldeionized water. The polymer was dissolved by stirring at 85°-100° C.with 500 ml deionized water. The solution was poured into a beaker andthe polymer was crystallized upon cooling. An additional 250 mldeionized water was added; the white gelatinous mass was stirredvigorously, and the polymer was collected by suction filtration.

The polymer was redissolved in 1.3 L of deionized water at 90° C. andagain allowed to crystallize, at which point it was filtered. Thisprocess of recrystallization and filtration was performed three times.The polymer was first air-dried then oven dried at 40-60° C. and at 25mm Hg for 5 days to give a yield of 97%. The resulting semi-transparentsolid was stored in an amber container kept in a dissecator. The polymerwas characterized using NMR, which established that the polymer islinear polyethyleneimine.

The resulted semi-transparent solid was poured into a flask to bedissolved in a hot (55-60° C.) chloroform/methanol solution (90%:10%ratio). Once the polymer is completely dissolved, the solution was thentransferred into another flask with an excess of ethyl ether toprecipitate the polymer. As soon as the polymer solution is in contactwith the ether, a white fine precipitate starts to show up. The ether isdecanted and the particles are dried under nitrogen. The bigger piecesof LPEI are scratched off the wall, mixed with dry ice (or liquidnitrogen), smashed in a mortar, and then transferred to a flask in orderto dry it under a stream of nitrogen. The product is passed through a 20mesh sieve and then stored in an amber container kept in a dissecator.

The NO modified compound was prepared by putting L-PEI as a particle,with acetonitrile in a high pressure glass bottle (ACE Glass) with amagnetic stir bar. The stirred mixture was purged with argon gas,depressurized, and then connected to a NO gas tank. The mixture was thenbrought to 80 psi of NO and left to react for 13 days under continuousstirring. After this time the NO gas was released, and the mixture waspurged and flushed with argon. The product was isolated by the removalof solvent using a roto evaporator and washed with ethyl ether threetimes. The resultant particles where analyzed using a Sievers 280i NOAnalyzer.

LPEINO particles (0.05 g) were suspended into a 20% (w/w) solution ofTecoflex polymer in ethanol and THF (80:20). The polymer solutions(LPEINO particles/Tecoflex polymer) were spun from a conical metalreservoir, which was suspended with copper wire that was connected tothe power supply, and the targeted plate was covered with aluminum foil;to facilitate the removal of the fiber. The diameter of the metal coneused to spun the nanofiber was 1.5 mm, the gap distance was 33 cm, and avoltage of 30 kV at room temperature. Same procedure was used to makethe fiber with Tecophilic polymer. Each of these released NO over timewhen subjected to activators.

Various modifications and alterations that do not depart from the scopeand spirit of this invention will become apparent to those skilled inthe art. This invention is not to be duly limited to the illustrativeembodiments set forth herein.

1. A medical device comprising: a polymeric carrier fiber, wherein thecarrier fiber is capable of reversibly reacting with nitric oxide; anitric oxide predrug; and a second fiber, wherein said second fiberfunctions to sequester said predrug from reactive species.
 2. Themedical device of claim 1, wherein the medical device is selected fromthe group consisting of a vascular graft, a stent, a catheter, and awound dressing.
 3. The medical device of claim 1, wherein the polymericcarrier fiber comprises at least one secondary amine moiety.
 4. Themedical device of claim 3, wherein the polymeric carrier fiber isselected from the group consisting of a polyethyleneimine, apolyethyleneimine grafted to a polysaccharide backbone, and apolyethyleneimine salt.
 5. The medical device of claim 3, wherein thepolymeric carrier fiber comprises a polyethyleneimine fiber.
 6. Thedevice of claim 3, wherein the polymeric carrier fiber comprises anelectrospun nanofiber.
 7. The device of claim 1, further comprising anactivator.
 8. The device of claim 1 further comprising a mobile phase.9. The device of claim 8, wherein the mobile phase is capable oftransporting an activator such that it contacts the nitric oxide predrugcomponent.
 10. The device of claim 9, wherein the mobile phase isselected from the group consisting of water, methanol, ethanol,propanols, butanols, pentanols, hexanols, phenols, naphthols, polyols,acetic acid, N,N-dimethylformamide, dimethyl sulfoxide,dimethylacetamide, and tetrahydrofuran, hexamethylphosphoramide.
 11. Thedevice of claim 1, wherein said second fiber is substantiallyhydrophobic.
 12. The device of claim 1, wherein the second fiber isselected from the group consisting of polyurethane, polyamide,polyethylene, polypropylene, polyesters, saturated polyesters,polyethylene terephthalate, polytetrafluoroethylene, perfluoroethylene,polystyrene, polyvinyl chloride, and polyvinyl pyrolidone.
 13. Thedevice of claim 1, wherein the second fiber imparts additional strength.14. The device of claim 13, wherein the second fiber imparts sufficientstrength to permit the device to be free-standing devices without theassistance of a substrate.
 15. The medical device of claim 1, whereinthe nitric oxide predrug component is selected from the group consistingof a diazeniumdiolate, an O-alkylated diazeniumdiolate, and anO-derivatized diazeniumdiolate.
 16. The medical device of claim 1,wherein the nitric oxide predrug component comprises a diazeniumdiolate.17. The device of claim 7, wherein the activator is a proton donor. 18.The device of claim 17, wherein the activator is a buffer selected fromthe group consisting of phosphates, succinates, carbonates, acetates,formates, propionates, butyrates, fatty acids, and amino acids.
 19. Thedevice of claim 17, wherein the activator is water.